The present invention relates to an apparatus comprising a closure-cap and a container in the form of a two-chamber cartridge in which an active ingredient and a solvent can be stored separately until the apparatus is used in a nebuliser, and to a propellant-free active substance concentrate in which the active ingredient is present in highly-concentrated form for storage purposes. The cartridge according to the invention serves especially as a container for medicament formulations for use in nebulisers for production of aerosols for inhalative or nasal application, especially for use in propellant-free nebulisers.
In the International Patent Application WO91/14468 xe2x80x9cAtomising Device and Methodsxe2x80x9d and also in WO 97/12687, cf. FIGS. 6a and 6B and the associated description, an apparatus for the propellant-free administration of a metered quantity of a fluid medicament for inhalative application is described. In such a nebuliser, a medicament solution is converted by means of high pressure into a lung-accessible aerosol and sprayed. For this kind of application, it can be necessary to decant the solutions which contain the active ingredients into containers so that only a small amount of air and gas residue is included. Containers which are suitable for this purpose, are, for example, disclosed in International Patent Application PCT/EP95/03183, to which express reference will be made for the purposes of the present invention. The containers described there are above all suitable for those medicaments which can be stored over a longer period of time in the form of an aqueous or ethanolic solution.
In order to increase the shelf-life of active ingredients in solution which break down after only a few months, DE 196 15 422 discloses a cartridge which has two chambers for the separate storage of the solvent and an active ingredient in the form of a powder or a compressed tablet. The cartridge is designed in such a way that when the cartridge is inserted in apparatus for the production of the aerosol (inhaler), the chamber which contains the active ingredient is penetrated by a canula in the inhaler, so that the active ingredient comes into contact with the solvent in the container and is dissolved. Although this cartridge for storing inhalation formulations in the aforementioned containers has many advantages, from time to time the canula of the inhaler, as specified, can become blocked when it penetrates the chamber which contains the active ingredient. For this reason, no medicament suspensions can be stored in the aforementioned chamber. Furthermore, it can not always be guaranteed that active ingredients formulated as a solid will dissolve sufficiently rapidly in the solvent, so that the desired active ingredient concentration can only be achieved with a time delay. In this way, trouble-free use of the inhaler charged with the cartridge is made difficult.
The present invention solves the aforementioned problems and also those known from the prior art in that a new two or multi-chamber cartridge (container) is provided where two or more components of the inhalation formulation can be stored separately from one another.
In particular, the invention relates to an apparatus comprising a closure-cap and a container which can be used as a cartridge (container) for nebulisers. In the cartridge, at least one active ingredient and one solvent of a therapeutic formulation specified for inhalative or nasal application can be stored separately until the cartridge is installed in the nebuliser as specified. As nebulisers, high-pressure atomisers and especially the high-pressure atomisers from WO91/14468 and WO 97/12687, FIGS. 6a and 6b and the associated description, are particularly suitable. Here, the cartridge is shaped so that the separately-stored components can be mixed together during use of the cartridge in the inhaler without causing a blockage of the canula, so that the medicament preparation is formed, ready for use, within the shortest possible time, preferably within a few minutes and possibly within a few seconds. In the context of the present invention, it is unimportant whether the medicament formulation which is to be applied is a solution or a suspension; what is critical is that the formulation which is to be applied is a fluid formulation which can be converted by means of a nebuliser of the aforementioned type into an aerosol for inhalative or nasal application. For administration by inhaling using the inhaler described hereinbefore, however, formulations in the form of solutions are generally preferred to those in the form of suspensions.
Within the scope of this description, the expressions nebuliser, atomiser, inhaler and high-pressure atomiser, and also metering aerosol and aerosol are used as synonyms unless otherwise stated.
The present invention is constructed in a similar manner to the invention in the aforementioned document DE 196 15 422, to the entirety of which reference will expressly be made. As in DE 196 15 422, the cartridge according to the invention has at least two possible ways of storing formulations or ingredients of formulations: the container of the cartridge and another chamber which is preferably formed in the closure-cap of the cartridge. Some ingredients of the formulation to be administered are stored in the chamber until ready for use, while the remaining ingredients are stored in the container, including the majority of the liquid component. This liquid component contains the solvent or suspension agent, or the majority thereof, provided for administration, preferably a solvent, and optionally other components which will be specifically described more fully hereinafter. By the term xe2x80x9cmajority thereofxe2x80x9d is meant that part of the formulation to be applied that is not already formulated together with the active substance in the chamber. In the following text, no great distinction is drawn between solvent and mixture of solvents, i.e. the term xe2x80x9csolventxe2x80x9d includes a mixture of solvents, unless otherwise stated. Conversely, however, a mixture of solvents always comprises at least two fluid, chemically-different components.
Active substances can be stored in a pharmaceutically-stable manner in the abovementioned chamber over a fairly long period of time of, for example, several months or possibly years, especially active ingredients which cannot be stored in a pharmaceutically stable manner in ethanolic solutions over the aforementioned time span.
The chamber is preferably formed in the closure-cap; however, it may be located elsewhere in the cartridge, e.g. in the interior of the container.
For reasons of clarity, in the course of this description the expression xe2x80x9cchamberxe2x80x9d is used for both a single chamber and also for a plurality of chambers of the same type located directly adjacent to one another, unless otherwise specified.
The chamber has at least one but preferably two openings. The closure-cap is designed so that the contents of the chambers can be transferred into the interior of the chamber through the one opening which is present in every case by means of an external influence, even when the closure-cap seals the container tightly. This opening is hereinafter referred to as the inner opening.
In addition, the chamber can optionally have a further opening. In the cartridge""s closed condition, a connection between the chamber and the external environment can be made by means of this opening, so that e.g. an object, such as e.g. a plunger, a stopper, a canula, a capillary or a rod can be introduced into the chamber from outside. This opening will hereinafter be referred to as the outer opening. It is expressly emphasised that the terms xe2x80x9cinner openingxe2x80x9d and xe2x80x9couter openingxe2x80x9d purely serve to differentiate between the terms, and no direct conclusions with regards to the position or the mutual orientation of the openings are to be made. If necessary, the inner opening can also take over the function of the outer opening.
In a preferred embodiment, the chamber is characterised in that at least one of the openings (or, in variants with only one opening, this opening) is connected to a movable plunger, sealing the opening tightly, which can be moved into or out of the chamber to open the chamber by means of an external canula or an external rod.
The inner opening of the chamber can be closed either by means of a movable stopper, a penetrable, easily-broken membrane or another movable sealing element. The outer opening optionally provided is sealed by a plunger, of such dimensions that it seals the chamber tightly on the one hand, but can be moved into the chamber by application of a force on the other hand.
In some embodiments, this plunger can have a hollow interior and have an opening. In these variants, the plunger can fill the entire chamber exactly and the active ingredient is then located inside it. If necessary, the plunger is arranged so that it simultaneously seals the outer opening and the inner opening tightly, and no further sealing elements are required to store the active ingredient, tightly sealed, within the cavity of the plunger.
When the cartridge is inserted in the inhaler, a canula or rod located in the inhaler penetrates the closure-cap and thereby directly or indirectly opens the sealing element of the inner opening. This can e.g. be achieved by the canula tearing, penetrating, opening or moving aside the sealing element, preferably starting from a point outside the chamber. If necessary, the canula can also open the sealing element from a point within the chamber. The sealing element may be a sealing foil, for example.
Alternatively, the canula may press the plunger into the chamber when the cartridge is inserted in the inhaler, so as to open the inner opening, e.g. the sealing element is either directly pierced, torn or opened by the plunger or is opened as a result of the over-pressure formed in the chamber. In doing this, the plunger is either pushed right through the chamber by the canula until it falls through the inner opening into the container, or it remains in the chamber in such a way that it does not interfere with the withdrawal of fluid through the canula.
Instead of the plunger sealing off the outer opening, one or more other equivalents can be used to perform the function of this element. These include stoppers, balls, spikes, platelets or seals of various types, e.g. sealing foils, clamp seals, plug seals or screw seals, or similar.
The apparatus according to the invention can be used as a cartridge for inhalers both for mono-preparations and also for combination preparations. In the case of mono-preparations, the active ingredient is preferably stored in a stable formulation in the chamber, the further ingredients of the pharmaceutical preparation to be applied, among them the majority of the liquid component, in the container. In the case of combined preparations, the active components can be stored as a stable formulation either in one single chamber or in various chambers. If the active ingredients which are used have significantly different shelf lives, the more sensitive active ingredient can be stored in the chamber, as described above. The other, more stable active ingredient can be stored together with the solvent or suspension agent located in the container. Naturally, a prerequisite of this is that the latter is stable in the solvent over the intended storage time of several months or years.
The shelf life of the cartridge thus filled can be substantially extended, compared with a cartridge containing the finished pharmaceutical preparation, by the delicate substances being stored in a different formulation from the one to be applied until the cartridge is inserted in the inhaler. An active substance can be stored in the chamber as a powder, granulate, in the form of a tablet, solution or as a suspension. Generally, for storage of the material or materials in the chamber, galenic formulations are preferred which promote simple and rapid dissolution of the active ingredient in the solvent when the two substances are brought together. Active substance concentrates are preferred, which constitute a further aspect of the present invention.
The active substance concentrate according to the invention contains one or more active substances which can be administered by inhalation and can preferably be used for inhalative therapy. The invention therefore also relates to the use of an active substance concentrate of this kind in inhalative therapy.
The active substance concentrate according to the invention may be converted, by dilution with a pharmacologically acceptable liquid optionally containing pharmaceutical excipients and additives, into a pharmaceutical preparation (aerosol formulation) which is converted into an inhalable aerosol with the aid of a nebuliser.
This diluent is preferably held in the container (2) when the cartridge according to the invention is used. The pharmaceutical preparation which is to be administered together with the active substance concentrate determines the precise composition of the diluent.
The active substance concentrate according to the invention refers to solutions or suspensions in which the active substance is dissolved or suspended in highly concentrated form in a pharmaceutically suitable liquid and which are characterised in that the active substance can be stored therein for a period ranging from several months to possibly several years without any deterioration in the pharmaceutical quality.
The term xe2x80x9cactive substance concentratexe2x80x9d denotes a solution or suspension of one or more active substances which is or are present in highly concentrated form in a pharmaceutically acceptable liquid as a solution or suspension. Suspensions are preferred, as they have proved particularly stable on storage.
The term xe2x80x9chighly concentratedxe2x80x9d denotes a concentration of the active substance which is usually too high to allow the corresponding solution or suspension to be used for inhalation for therapeutic purposes without being diluted. In the active substance concentrate, the concentration of the active substance (or substances) may exceed the concentration of the pharmaceutical preparation to be administered by a factor of 10 to 500, preferably 100 to 400, most preferably 250-350. According to the invention, the active substance concentration in the active substance concentrate for suspensions is between 10 mg/ml and 1000 mg/ml, preferably between 75 mg/ml and 1000 mg/ml, more preferably between 75 mg/ml and 500 mg/ml, most preferably between 100 mg/ml and 400 mg/ml, and most particularly between 250 mg/ml and 350 mg/ml. For solutions the range of concentrations is preferably between 10 mg/ml and 500 mg/ml, preferably between 75 mg/ml and 500 mg/ml, more preferably between 75 mg/ml and 200 mg/ml and most preferably between 75 mg/ml and 150 mg/ml. Thus, for example, formoterol can be present in one embodiment of the formulation according to the invention in a concentration of between 10 mg/ml and 500 mg/ml, preferably between 75 mg/ml and 500 mg/ml, more preferably between 100 mg/ml and 400 mg/ml and most preferably between 250 mg/ml and 350 mg/ml. For inhalation, purposes, this formulation then has to be diluted to a concentration of about 0.9 to 1.5 mg/ml. The concentration data relate to mg of free base formoterol per ml of active substance concentrate.
The active substance(s) may be any substances which are suitable for administration by inhalation and which are soluble or capable of being suspended in the abovementioned solvent or suspension agent. The preferred active substances are, in particular, betamimetics, anticholinergics, antiallergics, leukotriene antagonists and especially steroids and active ingredient combinations thereof.
Specific examples include:
Tiotropium bromide, 3-[(hydroxydi-2-thienylacetyl)oxy]-8,8-dimethyl-, 8-azoniabicyclo[3.2.1]oct-6-ene-bromide
1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino] ethanol,
erythro-5xe2x80x2-hydroxy-8xe2x80x2-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one,
1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butyl-amino)ethanol,
1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.butylamino)ethanol.
As anticholinergics:
Iprakopium bromide
Oxitropium bromide
Tropium chloride
N-∃-fluoroethylnortropine benzylate methobromide
As antiallergics:
Disodium cromoglycate
Nedocromil
Epinastin
9.alpha.-chloro-6-.alpha.-fluoro-11.beta.17.alpha.-dihydroxy-16.alpha.methyl-3-oxo-1,4-androstadiene-17.beta.-methylcarboxylate-17-propionate
Salbutamol, tiotropium and/or formoterol and the salts thereof, particularly formoterol, are preferably formulated in the concentrate as suspensions.
The term xe2x80x9cpharmacologically suitable fluidxe2x80x9d for the purposes of the present invention means a solvent or suspension agent which is not a liquefied propellant gas. Polar fluids are preferred, particularly protic fluids.
Examples of polar solvents or suspension agents for the active substance concentrate are e.g. dimethylsulphoxide or compounds which contain hydroxyl groups or other polar groups, e.g. water or alcoholsxe2x80x94particularly ethanol, isopropylalcohol, glycols, especially propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters etc.
Examples of protic liquids, which are the most preferred solvents or suspension agents in the context of the invention, are water, aqueous saline solutions with one or more pharmacologically acceptable salt(s), ethanol or a mixture thereof. In the case of aqueous ethanol mixtures, the ratio by volume of ethanol to water or to the aqueous saline solution is between 5:95 and 99:1, preferably between 40:60 and 96:4, most preferably between 75:25 and 96:4. A particularly preferred ratio is between 40:60 and 60:40.
For a saline solution as the solvent or suspension agent or as a component thereof, particularly suitable salts are those which display no or only negligibly little pharmacological activity after administration. Saline solutions are preferably used for suspension concentrates. The addition of the salt significantly reduces the dissolving power of water for the active substance or substances, so as to achieve a stabilising effect on the suspended particles. If desired, saturated saline solutions may be used. The quantity of salt depends on the precise composition of the solvent or suspension agent and its ability to dissolve the active substance. For example, formoterol should be present in dissolved form in an amount of less than 0.5% by weight, preferably less than 0.1% by weight, in an aqueous formoterol suspension in the sense of the active substance concentrate according to the invention, these amounts being based on the total amount (weight) of formoterol,. However, if the amount of dissolved material is above the specified levels, it can be reduced to below these levels by the addition of salt.
As a rule, the solubility can be halved by the addition of salt, and in some cases reduced to one fifth or even less. Preferred are saline solutions with a salt content of up to 50% by weight, especially up to 20% by weight.
Both inorganic and organic salts may be used as the salts. Inorganic salts such as sodium chloride, alkali metal or ammonium halogen salts are preferred. Sodium chloride is particularly preferred. Suitable organic salts are, for example, the sodium, potassium or ammonium salts of the following acids: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid.
Cosolvents may be added to the solvent or suspension agent. Co-solvents are suitable for increasing the solubility of additives and optionally the active substance (or substances).
Preferred cosolvents are those which contain hydroxyl groups or other polar groups, for example alcoholsxe2x80x94especially isopropyl alcohol, glycolsxe2x80x94especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters, provided that these are not already used as the solvent or suspension agent.
Other excipients and additives may also be added to the active substance concentrate according to the invention.
The term excipients and additives in this context denotes any pharmacologically suitable and therapeutically useful substance which is not an active substance but can be formulated together with the active substance (or substances) in the pharmacologically suitable solvent or suspension agent in order to improve the qualitative properties of the active substance concentrate or the pharmaceutical preparation which is to be obtained by dilution ready for inhalation. Preferably, these substances have no pharmacological activity or, in the context of the desired therapy, no appreciable or at least no undesirable pharmacological activity. The excipients and additives include, for example, surfactants for stabilising suspensions, other stabilisers, complexing agents, antioxidants and/or preservatives which prolong the duration of use of the finished pharmaceutical formulation, flavourings, vitamins, and/or other additives known in the prior art.
As surfactants the active substance concentrate may contain, for example, soya lecithin, oleic acid, sorbitan esters such as sorbitan trioleate or other surfactants known from the prior art in the usual concentrations.
It has been found that addition of an organic or inorganic acid, preferably in combination with a complexing agent, leads to improvement in the stability (shelf life) of some medicaments which contain ethanol as a solvent, especially medicaments containing steroids. This applies especially to medicament preparations which contain formoterol, flunisolide or its hydrate or hemihydrate or budenoside as active ingredient.
Examples of inorganic acids which are preferred in this respect are: hydrochloric acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples of especially suitable organic acids are: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid, propionic acid and others. The preferred acids are hydrochloric acid and/or fumaric acid.
The concentration of acid is selected so that the active substance concentrate has a pH of between 2.0 and 7.0, preferably between 4.0 and 6.0 and most preferably between 4.5 and 5.5.
Examples of complexing agents which may be used on their own or in conjunction with an acid include EDTA (ethylenediaminetetraacetic acid, or a salt thereof, such as the disodium salt), citric acid, nitrilotriacetic acid and the salts thereof. The preferred complexing agent is EDTA.
Preservatives can be used to protect the concentrate from contamination with pathogenic germs. Those preservatives which are known in the prior art are suitable, especially benzalkonium chloride or benzoic acid, or benzoates such as sodium benzoate.
Suitable antioxidants are the well known pharmacologically acceptable antioxidants, especially vitamins or provitamins, as present in the human body, i.e. ascorbic acid or vitamin E.
If the active substance or substances is or are present in the active substance concentrate according to the invention as a suspension, the particles are preferably formulated in a particle size of up to 20 :m, preferably up to 10 :m and especially preferably up to 5 :m.
Preferred active substance concentrates contain only one or two active substances; active substance concentrates having one active substance are particularly preferred.
Suspensions are most preferred as the active substance concentrate.
The active substance concentrate according to the invention has the advantage that an active substance can be formulated in such a way as to remain stable over a fairly long period of time. It is not necessary for the concentrate to correspond to the composition of the finished pharmaceutical preparation, apart from the concentration of the active substance. For example, the pH of the concentrate may differ substantially from the pH of the pharmaceutical preparation which is to be administered, if this ensures a more stable solution or suspension of an active substance.
The active substance concentrate according to the invention is not usually suitable as such for direct medicinal use, particularly for inhalation. As already explained, use of the active substance concentrate comprises converting it into a pharmaceutical preparation (aerosol formulation). The term xe2x80x9cpharmaceutical preparationxe2x80x9d denotes a formulation of a pharmaceutical substance suitable for inhalation wherein a pharmaceutical substance or mixture of substances can be administered in the required and/or recommended concentration.
The pharmaceutical preparation is preferably such that it can be administered by inhalation using a suitable nebuliser.
A preferred method of converting the active substance concentrate into a pharmaceutical preparation suitable for administration is by diluting the active substance concentrate according to the invention with a pharmacologically suitable solvent or suspension agent.
In order to obtain the pharmaceutical preparation for administration, the active substance concentrate is diluted until the pharmaceutical preparation ready for inhalation is produced. The pharmaceutical preparation to be administered determines, together with the active substance concentrate in the chamber (17), the precise composition of the diluent in the container (2).
Examples of formulations which are suitable for administration are disclosed in WO 97/01329, to the contents of which reference is expressly made. If such formulations are to be administered within the context of the present invention, the active substance concentrate in the chamber (17) and the diluent in the container (2) should be such that when they are mixed together they produce a formulation according to or analogous to that of WO 97/01329.
In a formulation of this kind suitable for administration, the proportion of dissolved medicament in the finished pharmaceutical preparation is generally between 0.001 and 5%, preferably between 0.05 and 3%, particularly between 0.01 and 2%, these figures referring to percent by weight. In the case of solutions as the finished pharmaceutical preparation the maximum concentration of the medicament is dependent on the solubility in the solvent and the dosage required to achieve the desired therapeutic effect.
As already mentioned, aqueous or aqueous saline solutions, preferably aqueous solutions, which may contain ethanol, are preferred inter alia as solvents or suspension agents for the finished pharmaceutical preparation, i.e. the preparation suitable for inhalative or nasal application. Solutions with at least 30% (v/v) ethanol are preferred, and especially preferably with at least 50% (v/v). Especially preferred are solutions with an ethanol content of over 95% (v/v). Concentration is given in percent by volume (v/v) , the remainder being water or aqueous saline solution. Ethanol which already contains small quantities of water is especially preferredxe2x80x94for example 96% ethanol, 4% water (v/v)xe2x80x94so that it is no longer hygroscopic and evaporates azeotropically.
The pharmaceutical preparation to be applied together with the active substance concentrate in the chamber (17) determine the exact composition of the diluent in the container (2).
The medicament formulation ready for use is only prepared when the cartridge is inserted in the inhaler for it is only by this action that the contents of the chamber (17) are mixed with those of the container (2). It should be pointed out here that the individual components or ingredients of the diluent are defined as specified in connection with the active substance concentrate, where these components or ingredients have been described or unless otherwise specified.
Preferred solvents or suspension agents for the dilution are propellant-free liquids, preferably polar, more particularly protic liquids.
Particularly preferred diluents are water, aqueous saline solutions with one or more pharmacologically acceptable salts, ethanol or a mixture thereof, mixtures of water and ethanol being particularly preferred. In the case of aqueous ethanol mixtures, the ratio by volume of ethanol to water or to the aqueous saline solution is such that the inhalable pharmaceutical preparation has a formulation with at least 30% (v/v) ethanol, most preferably with at least 50% (v/v). Especially preferred are pharmaceutical preparations with an ethanol content of over 95% (v/v). Concentration is given in percent by volume (v/v) , the remainder being water or aqueous saline solution. Ethanol which already contains small quantities of water is especially preferredxe2x80x94for example 96% ethanolxe2x80x94so that it is no longer hygroscopic and evaporates azeotropically.
It is neither obvious nor necessary for the diluent to be identical to the solvent or suspension agent of the active substance concentrate. If desired, the latter may also contain only one or a few constituents of the diluent.
It should be expressly pointed out here that the cosolvents and/or excipients or additives and/or active substances mentioned above in connection with the active substance concentrate according to the invention may also or only be dissolved or suspended in the diluent.
Preferred embodiments of the diluent contain preservatives and/or complexing agents.
Optionally, the diluent may contain a buffer substance, e.g. trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, Na-EDTA, EDTA, mixtures thereof and other substances known from the prior art. Preferred substances are sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium hydrogen phosphate, potassium dihydrogen phosphate, potassium hydrogen phosphate, tripotassium hydrogen phosphate, and mixtures thereof. Buffer substances are particularly beneficial when the active substance concentrate suitable for storage according to the invention has a pH which differs significantly from that which is desired for the application, e.g. when this increases the stability of the active substance during storage. In this case the buffer substance is present in the diluent in a concentration such that, after mixing the active substance concentrate with the diluent, an aerosol formulation suitable for administration is obtained with the desired pH, preferably between 2.0 and 7.0, particularly between 4.0 and 6.0. most preferably between 4.5 and 5.5.
In a preferred embodiment, the pharmaceutical preparation contains a complexing agent which is preferably selected from a complexing agent mentioned in connection with the active substance concentrate. The quantity of complexing agent is up to 100 mg/100 ml, preferably up to 50 mg/100 ml. The preferred complexing agent is EDTA.
A preferred pharmaceutical preparation contains, for example, in the pharmaceutical preparation which is to be administered, 1.667% by weight of flunisolide, 0.01 mg/100 ml EDTA and ethanol (96% v/v) as solvent. It is adjusted to a pH of between 3.0 and 4.0, preferably 4.0, by the addition of acid (hydrochloric acid).
If the diluent contains one or more active substances, the diluent may contain an organic or inorganic acid, preferably combined with a complexing agent, as a stabiliser, particularly in the case of steroid-containing drugs. This applies particularly to pharmaceutical preparations which contain formoterol, flunisolide or the hydrate or hemihydrate thereof or budesonide as active substance.
As already mentioned, the pharmaceutical preparation which is to be administered together with the active substance concentrate determines the precise composition of the diluent.
Preferred pharmaceutical preparations contain one or two active substances; pharmaceutical preparations having one active substance are particularly preferred.
Neither the active substance concentrate suitable for storage according to the invention nor the pharmaceutical preparation for administration obtained by dilution contains a propellant.
Preferably, the mixing takes place at ambient temperature and under normal pressure. One advantage of the active substance concentrate according to the invention is that it can be converted by dilution into a therapeutically effective formulation and/or one which is suitable for use in a nebuliser within a very short time, e.g. within a few minutes or possibly a few seconds. The mixing can also be done by patients, who generally have no pharmaceutical knowledge.
Alternatively to the separation of the individual components of the pharmaceutical preparation to be administered, as described earlier, for the purpose of inhalation, the active substance may also be stored in the container (2), preferably as a storable solution or suspension, which does not necessarily constitute the pharmaceutical preparation to be administered. In this case, the concentration of the active substances corresponds to the concentration of the pharmaceutical preparation to be administered as described above (plus or minus 10% by weight). The chamber (17) then contains the other excipients and additives, preferably those mentioned above, for producing the pharmaceutical preparation which is to be administered. These may then take the form of powders, tablets, suspensions or solutions.
For example, an active substance may be stored as a solution or suspension in the container (2) at a pH which is more acidic or more basic than that of the pharmaceutical preparation to be administered. In this case, the chamber (17) may contain buffers, for example, preferably those described above. When the cartridge is inserted in the inhaler, the pH desired for administration is achieved by mixing the contents of the chamber (17) with the formulation in the container (2). For example, a liquid formulation containing tiotropium bromide as active substance may be stored in the container (2) at a pH of less than or equal to 3.0. The chamber (17) then contains buffer substances such as those mentioned above, e.g. the sodium and potassium di- and mono-hydrogen phosphates, in an amount which ensures that a pH of from 3.0 to 7.0, preferably from 3.0 to 4.0, is obtained when these buffers are mixed with the tiotropium formulation. These figures are merely an example of the formulation possibilities for tiotropium bromide and are not necessarily identical for other active substances mentioned. The active substance can also be stored in the container (2) as a suspension while the chamber (17) contains a pharmacologically acceptable solvent, so that a solution formulation is produced when they are mixed together.
The preferred volume of the formulations in the chamber (17) and container (2) is crucially determined by the volumes of the chamber (17) and container (2). For storage in the abovementioned cartridge, in preferred embodiments, the quantity of active substance concentrate suitable for storage according to the invention is selected to correspond to a volume of 0.001 to about 0.05 ml, preferably 0.001 to 0.02 ml.
The abovementioned examples demonstrate that the two-chamber cartridge can be used to store different components of an active substance formulation separately until the cartridge is inserted in the appropriate inhaler. It is not necessary for the components thus stored to be capable of being administered per se. All that is required is that the components thus stored are mixed together when the cartridge is inserted in the appropriate inhaler so as to produce the desired formulation ready for administration.